Method of treating coronary arteries with perivascular delivery of therapeutic agents

ABSTRACT

A method of treating the intraluminal disease in a coronary artery by injecting therapeutic agents perivascularly into the myocardium near the site of disease.

This application is continuation of U.S. application Ser. No.10/671,270, file Sep. 24, 2003, now U.S. Pat. No. 7,998,105, which isdivisional application of U.S. application Ser. No. 10/353,117 filedJan. 27, 2003, which is a continuation of U.S. application Ser. No.09/407,461 file Sep. 28, 1999, now U.S. Pat. No. 6,511,477.

FIELD OF THE INVENTION

The present invention relates to the interstitial delivery ofparticulate drug delivery systems for large and small moleculetherapeutic agents within the heart.

BACKGROUND OF THE INVENTION

Local drug delivery provides many advantages. Approaches for localcontrolled release of agents at a depth within a tissue such as theheart, pancreas, esophagus, stomach, colon, large intestine, or othertissue structure to be accessed via a controllable catheter will deliverdrugs to the sites where they are most needed, reduce the amount of drugrequired, increase the therapeutic index, and control the time course ofagent delivery. These, in turn, improve the viability of the drugs,lower the amount (and cost) of agents, reduce systemic effects, reducethe chance of drug-drug interactions, lower the risk to patients, andallow the physician to more precisely control the effects induced. Suchlocal delivery may mimic endogenous modes of release, and address theissues of agent toxicity and short half lives.

Local drug delivery to the heart is known. In U.S. Pat. No. 5,551,427,issued to Altman, implantable substrates for local drug delivery at adepth within the heart are described. The patent shows an implantablehelically coiled injection needle which can be screwed into the heartwall and connected to an implanted drug reservoir outside the heart.This system allows injection of drugs directly into the wall of theheart acutely by injection from the proximal end, or on an ongoing basisby a proximally located implantable subcutaneous port reservoir, orpumping mechanism. The patent also describes implantable structurescoated with coating which releases bioactive agents into the myocardium.This drug delivery may be performed by a number of techniques, amongthem infusion through a fluid pathway, and delivery from controlledrelease matrices at a depth within the heart. Controlled releasematrices are drug polymer composites in which a pharmacological agent isdispersed throughout a pharmacologically inert polymer substrate.Sustained drug release takes place via particle dissolution and sloweddiffusion through the pores of the base polymer. Pending applicationSer. Nos. 08/8816850 by Altman and Altman, and 09/057,060 by Altmandescribes some additional techniques for delivering pharmacologicalagents locally to the heart. Implantable drug delivery systems, such ascontrolled release matrices, have been well described in the literature,as has the use of delivering particulate delivery systems or particulatedrug carriers such as microcapsules, lipid emulsions, microspheres,nanocapsules, liposomes, and lipoproteins into the circulating blood.However, local delivery of such micro drug delivery systems to a depthwithin the myocardium using endocardial catheter delivery and epicardialinjection systems have not been described, and have many advantages thathave not been foreseen.

Recently, local delivery to the heart has been reported of therapeuticmacromolecular biological agents by Lazarous [Circulation, 1996,94:1074-1082.], plasmids by Lin [Circulation, 1990; 82:2217-2221], andviral vectors by French [Circulation, Vol. 90, No 5, November 1994,2414-2424] and Muhlhauser [Gene Therapy (1996) 3, 145-153]. March[Circulation, Vol. 89, No 5, May 1994, 1929-1933.] describes thepotential for microsphere delivery to the vessels of the heart, such asto limit restenosis, and this approach has also been used for thedelivery of bFGF by Arras [Margarete Arras et. al., The delivery ofangiogenic factors to the heart by microsphere therapy, NatureBiotechnology, Volume 16, February 1998.] These approaches formicrosphere delivery obstruct flow, and will be delivered preferentiallyto capillary beds which are well perfused. Further, these approaches donot deliver therapeutic agents to the interstitial spaces. None of thiswork recognizes the potential to use particulate drug delivery system tooptimize local drug delivery at a depth within the myocardium. This artalso does not recognize the potential such delivery systems have intreating disease substrates in the myocardium if delivered to anappropriate region of the myocardial interstitium.

Problems exist for delivering small molecules or lipophilic moleculeswhich rapidly transport through the capillary wall, to well-perfusedtissues such as the myocardium. These problems are due to the convectivelosses of the agents to the systemic circulation. By going rapidlyacross the capillary wall, the small molecules are rapidly carried awayby the bloodstream. Local delivery of an easily transported molecule isdifficult because local delivery concentrations are rapidly reduced atvery small distances from the delivery site due to convective losses.Such easily transported agents cannot treat an effective area of tissuelocally without raising the systemic concentrations of the agents to atherapeutic level.

SUMMARY

The therapeutic compounds described below comprise very small capsuleswhich can be injected into body tissue, particularly the heart. Thecapsules include an encapsulating layer which surrounds a therapeuticagent. After injection, the encapsulating layer degrades or dissolves,and the therapeutic agent is released within the heart. The therapeuticagent may be one of any number of known agents such as anti-arrhythmicdrugs, gene therapy solutions, and macromolecules intended to haveeither acute or long-term effects on the heart. While some of thesetherapeutic agents are used to treat the heart by injecting them intothe heart, they are of such small size that they readily enter thecardiac capillary system and the cardiac lymphatic system, and arequickly transported away from the injection site. Thus, in priortreatment methods, relatively large doses and repeated doses arerequired to provide therapeutic effect at the injection site. To providea solution to this problem, the capsules described below are provided insizes that are too large to permit capillary transport or lymphatictransport. Thus, injected capsules are immobile within the heart tissue,and upon degradation they will release a therapeutic agent very near thesite of injection. The capsules may also be provided in sizes that aretoo large to permit capillary transport, but small enough to enter thelymphatic system and be transported away from the injection site in thecardiac lymphatic system, so that the therapeutic effect is provided atsome distance from the injection site. The encapsulating layer may bemade from various materials including biodegradable polymers in the formof microspheres, or from standard vesicle forming lipids which formliposomes and micelles.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an encapsulated therapeutic agent designed forinjection into the heart.

FIG. 1 a illustrates a microsphere encapsulated therapeutic agentdesigned for injection into the heart.

FIG. 2 illustrates a method for injection of therapeutic agents into theheart.

FIG. 3 illustrates the expected transportation of molecules releasedfrom degrading microspheres injected within the myocardium.

FIGS. 4 a through 4 d illustrate the progression of injected liposomeencapsulated small molecules within the heart tissue after injection.

FIG. 5 illustrates a method of delivering therapeutic agents to thecoronary arteries through the lymphatic vessels.

FIG. 6 is a like view showing the balloon angioplasty.

FIG. 7 is a like view showing a deployed stent.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 illustrates a microdrug delivery system which is comprised of acompound or substance for use in delivering a therapeutic agent to theheart. The compound is comprised of numerous capsules i which are madeup of an encapsulating layer ii which may form a microsphere formulatedfrom Prolease™ or other biodegradable microsphere material, or fromvesicle forming lipids which may form a liposome or micelle, and atherapeutic agent iii within the encapsulating layer. Therapeutic agentmay be embedded in a biodegradable polymer, or in a carrier fluid 4. Theencapsulating layer is typically pharmacologically inactive, althoughtechniques to make it active to promote cellular uptake and/or receptorbinding are known in the art. The therapeutic agent may be any of a widevariety of drugs and other compounds used for treatment of variousailments of the heart. The capsules are carried within a solution suchas pH controlled saline to create a slurry which can be injected intothe heart of a patient. Prior to injection, the encapsulating layer willprotect the macromolecule from mechanical and chemical degradationwithin the catheter or needle used for injection. Once injected into theheart tissue, the size of the encapsulating layer will inhibit transportof the compound away from the injection site, either through the cardiaccapillary system and/or the cardiac lymphatic system. Also onceinjected, the encapsulating layer will degrade, either due to chemicalconditions, biological conditions, or temperature conditions within theheart wall, and release the encapsulated molecule. The time period overwhich the encapsulating layer degrades is variable, depending upon itsformulation, such formulations being available in the art. The half-lifefor degradation may be selected from several minutes to several days,depending on the therapy intended. Thus a sustained reservoir oftherapeutic agent is created within the heart tissue near the injectionsite, and therapeutic agents are slowly released near the injection siteto treat nearby tissue. The need to flood the entire heart and/or theentire blood system of the patient is eliminated, so that very smalldoses of therapeutic agents are enabled. This reduces the cost oftreatment, and minimizes the otherwise harsh side effects associatedwith many effective therapeutic agents.

FIG. 1 a illustrates the formulation of the microdrug delivery systemfrom a microsphere formulated from Prolease™, biodegradable polymers, orparticulate controlled release matrix with molecules of therapeuticagent dispersed throughout the microsphere. The microsphere 5 in FIG. 1a includes numerous molecules or particles of therapeutic agents iiidispersed throughout the solid biodegradable microsphere or particulatecontrolled release matrix 6. As the microsphere material degrades,therapeutic agents are slowly released from the microsphere. Thisformulation differs from the capsule formulation, but may be employed toachieve similar results. In one preferred embodiment, the core 7 of thesolid biodegradable microsphere contains no therapeutic drug at a radiusless then approximately 20 um, preferably about 15 um. Thus the core ofthe microsphere, to a radius of up to 20 um, preferably 15 um, may bedevoid of therapeutic agent. Alternatively, the core of the microsphere,to a radius of up to 10 um, preferably 7.5 um, may be devoid oftherapeutic agent. This prevents problems associated with migration ofthe potentially potent depot within the lymphatic system. The core ofthe microsphere may also be designed to have a longer degradationhalf-life so that essentially all of the drug will be delivered beforethe microsphere can substantially migrate through the lymphaticnetworks. Thus, the particulate micro delivery systems includesmillispheres, microspheres, nanospheres, nanoparticles, liposomes andmicelles, cellular material and other small particulate controlledrelease structures which can be advanced in a fluid suspension or slurryand be delivered to a depth within the heart muscle. These small drugdelivery systems may deliver therapeutic agents as diverse as smallmolecule antiarrhythmics, agents that promote angiogenesis, and agentsthat inhibit restenosis. They may also be combined in cocktails withsteroid agents such as dexamethasome sodium phosphate to preventinflammatory response to the implanted materials. Separate particulatedrug delivery systems for delivering different agents to the same regionof the heart may also be used. The release kinetics of separate microdelivery systems may also be different.

Delivery of small drug delivery systems reduce the likelihood of causingembolic events in the brain, kidneys, or other organs should these drugdelivery systems escape into the left chambers of the heart. Because thesystems are small only very small arterioles would be occluded shouldone of them escape into the blood within the left chambers of the heart.This is not a problem in the right side of the heart, as the lungs actas a filter of potentially embolic materials.

FIG. 2 shows a catheter system 9 with centrally located drug deliverycatheter 20 implanted at a depth within the left ventricular apex 15 ofthe heart 10. Hollow penetrating structure 30 has penetrated the heartmuscle, and has transported particulate encapsulated agents 35 such asVEGF, bFGF, or other therapeutic agent to a depth within the heartmuscle. The encapsulated agents are injected into the heart muscle (themyocardium) in an intact portion of the heart muscle (that is, not intoa vessel such as the ventricle chamber, a coronary artery or a TMRchannel which are subject to blood flow and immediate transport of theinjected particles from the area). The capsules or microspheres aresuspended within a fluid inside the catheter to facilitate injection.The use of small drug delivery systems in slurry or suspension deliveredby a fluidic pathway (a needle or catheter) to a depth within themyocardium can solve different problems in pharmacokinetics of localcardiovascular drug delivery. Such an approach can provide for wellcontrolled and easily administered sustained dosage of therapeuticmacromolecules, eliminate the issue of convective losses of smallmolecules for local delivery, and increase the ability of gene therapypreparations to gain access through the cell membrane.

Problems exist for macromolecular therapies in the heart such as shorthalf-lives and the presence of endogenous inhibitors. Manymacromolecular therapies may be improved by providing a sustained dosageover time to overcome endogenous inhibitors, as well as encapsulation toprotect the macromolecule from degradation.

The interstitial (intramuscular or intra-myocardial) delivery ofparticulate drug delivery systems for sustained release such asbiodegradable microspheres solves these problems. Particulate systems,such as microspheres, enable the time course of delivery and area oftreatment to be controlled. In addition, such particulate systems may bedelivered to the target site by a fluid pathway within a drug deliverycatheter such as those described in the prior art. The advantages ofthese particulate delivery systems is that they are implanted at a depthwithin the heart tissue and the implanted catheter device can be removedimmediately. Thus, a very quick procedure may be performed on anoutpatient basis to deliver particulate drug delivery systems to a depthwithin a patient's heart for sustained delivery measured in days toweeks.

The microspheres to be used in this treatment are manufactured to belarge enough to prevent migration within the myocardial interstitium,but also small enough to be deliverable by a catheter fluid pathway to adepth with the myocardium. Microspheres such as Alkerme's (Cambridge,Mass.) Prolease system enable freeze dried protein powder to behomogenized in organic solvent and sprayed to manufacture microspheresin the range of 20 to 90 um (microns). Development of such microspheredepots for sustained release of proteins with unaltered integrityrequires methods to maintain stability during purification, storage,during encapsulation, and after administration. Many of these techniqueshave been recently summarized in the literature. See, e.g., Scott D.Putney, and Paul A. Burke: Improving protein therapeutics with sustainedrelease formulations, Nature Biotechnology, Volume 16, February 1998,153-157. Issues associated with degradation for biodegradable polymersused in such microspheres are also well known [Robert Miller, JohnBrady, and Duane E. Cutright: Degradation Rates of Oral resorbableImplants {Polylactates and Polyglycolates}: Rate Modification andChanges in PLA/PGA Copolymer Ratios, J. Biomed. Mater. Res., Vol. II,PP. 711-719 (1977). The value of delivering microsphere encapsulatedmacromolecular agents such as proteins bFGF and VEGF to a depth withinthe heart muscle for controlled release have not been described, andhave substantial unrecognized benefits over other delivery approaches.

FIG. 3 shows a schematic description of microsphere encapsulated agentsfor delivery. Macromolecule angiogenic agents 336 such as VEGF and bFGFare delivered with biodegradable microspheres 335 in combination withbiodegradable microspheres 302 enclosing dexamethasone sodium phosphateor other anti inflammatory steroid. In other embodiments theanti-inflammatory agents may be combined with a particular therapeuticwithin the same encapsulation. The microspheres are injected through theendocardium 338 and into the myocardium 339 so that they resideinterstitially within the heart tissue. Both microspheres 335 and 302are too large to be transported away by either the capillary system orthe lymphatic system from the injection site within the myocardium.Where the microspheres are greater than about 15 micrometers indiameter, they will remain at the injection site and will not migrate.Where the microspheres have a diameter less than about 1 micrometer theywill migrate in the cardiac lymphatic system, but will not enter thecardiac capillary system. As the microspheres degrade over time, theircomponents and the therapeutic molecules will be transported away fromthe injection site by the myocardial lymphatic system which has beendescribed in relation to the transport of extravasated proteins from theendocardium 338 to the epicardium 340, and from the apex of the heart345 towards the base of the heart 350. [Albert J. Miller, Lymphatics ofthe Heart, Raven Press, New York, 1982.] Here the microspheres aredelivered endocardially and inferiorly (that is, upstream in thelymphatic system) to the region to be treated, identified hereschematically by window 355. Clearly regions within window 355 andregions directly adjacent to the window will all result in effectivedelivery of agents to the desired target, and are viable approaches aswell. The large molecules delivered in such a fashion will betransported through the lymphatics far more slowly than small moleculeswhich would be more rapidly convected away from the delivery region bythe blood supply. But approaches exist to minimize the issues associatedwith convective losses of small molecules.

The method of packaging the small molecule so that it cannot beconvected away by the blood, yet will be distributed locally in thetissue, and then effecting its action on the tissue can be accomplishedwith liposomal encapsulation. The term “liposome” refers to anapproximately spherically shaped bilayer structure, or vesicle,comprised of a natural or synthetic phospholipid membrane or membranes,and sometimes other membrane components such as cholesterol and protein,which can act as a physical reservoir for drugs. These drugs may besequestered in the liposome membrane or may be encapsulated in theaqueous interior of the vesicle. Liposomes are characterized accordingto size and number of membrane bilayers. Vesicle diameters can be large(>200 nm) or small (<50 nm) and the bilayer can have unilamellar,oligolamellar, or multilamellar membrane.

Liposomes are formed from standard vesicle forming lipids, whichgenerally include neutral and negatively charged phospholipids with orwithout a sterol, such as cholesterol. The selection of lipids isgenerally guided by considerations of liposome size and ease of liposomesizing, and lipid and water soluble drug release rates from the site ofliposome delivery. Typically, the major phospholipid components in theliposomes are phosphatidylcholine (PC), phosphatidylglycerol (PG),phosphatidyl serine (PS), phosphatidylinositol (PI) or egg yolk lecithin(EYL). PC, PG, PS, and PI having a variety of acyl chains groups orvarying chain lengths are commercially available, or may be isolated orsynthesized by known techniques. The degree of saturation can beimportant since hydrogenated PL (HPL) components have greater stiffnessthan do unhydrogenated PL components; this means that liposomes madewith HPL components will be more rigid. In addition, less saturated Plsare more easily extruded, which can be a desirable property particularlywhen liposomes must be sized below 300 nm.

Current methods of drug delivery by liposomes require that the liposomecarrier will ultimately become permeable and release the encapsulateddrug. This can be accomplished in a passive manner in which the liposomemembrane degrades over time through the action of agents in the body.Every liposome composition will have a characteristic half-life in thecirculation or at other sites in the body. In contrast to passive drugrelease, active drug release involves using an agent to induce apermeability change in the liposome vesicle. In addition, liposomemembranes can be made which become destabilized when the environmentbecomes destabilized near the liposome membrane (Proc. Nat. Acad. Sci.84, 7851 (1987); Biochemistry 28: 9508, (1989).) For example, whenliposomes are endocytosed by a target cell they can be routed to acidicendosomes which will destabilize the liposomes and result in drugrelease. Alternatively, the liposome membrane can be chemically modifiedsuch that an enzyme is placed as a coating on the membrane which slowlydestabilizes the liposome (The FASEB Journal, 4:2544 (1990). It is alsowell known that lipid components of liposomes promote peroxidative andfree radical reactions which cause progressive degradation of theliposomes, and has been described in U.S. Pat. No. 4,797,285. The extentof free radical damage can be reduced by the addition of a protectiveagent such as a lipophilic free radical quencher is added to the lipidcomponents in preparing the liposomes. Such protectors of liposome arealso described in U.S. Pat. No. 5,190,761, which also describes methodsand references for standard liposome preparation and sizing by a numberof techniques. Protectors of liposomal integrity will increase the timecourse of delivery and provide for increased transit time within thetarget tissue.

Liposomal encapsulation of small molecules makes local deliverypossible. By having a liposomal preparation which is unstable in thebody, it will collapse after it is delivered. Liposomes can beconstructed in varying size, including the size range less than 400 nm,preferably 200-250 nm. Between the time of delivery and the time ofcollapse, the liposomes in the size range less than 400 nm will betransported into and through the lymphatics and provide forredistribution of small molecules. Delivery of liposomes that degraderapidly once delivered to the body in a matter of minutes goes againstthe typical approaches for liposomal delivery and design. Typically pHsensitive liposomes involves the destabilization of the liposome in theendosome as the pH falls from physiological 7.4 to 5.0, while here weare describing liposomes which become destabilized near pH 7.4.[Chun-Jung Chu and Francis C. Szoka: pH Sensitive Liposomes, Journal ofLiposome Research, 4(1), 361-395 (1994)].

FIG. 4 a shows a schematic of the delivery of small molecules withinliposomes which are unstable at physiological pH (the pH of the hearttissue or the physiological environment into which the molecules aredelivered). A guiding catheter 401 is shown with a single lumen needledrug delivery catheter 402 containing liposome encapsulated smallmolecules 403 which are delivered through needle 404 by way of needlefitting 404. Here the penetrating needle 405, crosses the endocardium410 to deliver liposomes 415 to a depth within the heart wall 420.Although the liposomes could be various sizes and have a number of lipidbilayers, in the preferred embodiment they are small unilamellarliposome vesicles (SUVs) to augment their rapid uptake by the cardiaclymphatic system. The drug delivery catheter 402 contains liposomesbathed in a solution at their stable pH so that they do not collapseprematurely. FIG. 4 b shows that the catheter has been removed and thatthe uptake of the SUVs 415 by a lymphatic vessel 425 at some time t2later than the time they were delivered t1 to the myocardialinterstitium, such as the subendocardial interstitium. Of course, otherphysiochemical properties could be used such that the liposomalpreparations are delivered from a system in which they are stable to asystem at a depth within the heart with different physio-chemicalproperties in which they are unstable. Temperature is another possibleproperty that could be varied. Arrows near 407 show that lymphatictransport is from endocardium to epicardium and from apex to base in theheart. The lymphatic transport will carry the encapsulated smallmolecules a distance which will be governed by their stability and meantime to liposomal degradation. FIG. 4 c shows the same tissue in alarger view at time t3 later than time t2 in which SUVs 415 aredegrading and releasing small molecule drugs 430 within the lymphatics.The spread of the released drug in the degraded liposomes 430 providestherapeutic treatment to a large region of heart tissue while systemiceffects are minimized. FIG. 4 d shows that upon degradation, the smallmolecules 430 will be transported through the lymphatic vessel wall 435to the adjacent myocytes, and be convected rapidly away from the region.This transport through the lymphatic walls is shown schematically by thelarge arrows at the site of the degraded liposome with released smallmolecules. Because of the inability of the small molecules to beconvected away rapidly until the liposome collapses, a much largerregion of tissue will be able to be treated locally than by localinfusion of the small molecules themselves. In one embodiment, oleicacid (OA) and dioleoylphosphatidyl-ethanolamine (DOPE) devoid ofcholesterol which have been shown to be extremely unstable in thepresence of body fluid plasma [Liu, D. and Huang, L., Role OfCholesterol In The Stability Of pH Sensitive, Large UnilamellarLiposomes Prepared By The Detergent-Dialysis Method, Biochim Biophys.Act, 981, 254-260 (1989)] and could be used to encapsulate smallmolecule gene regulators such as hormones or antiarrhythmic agents.

In another embodiment, liposomes of dimyristoyl-phosphatidylcholine(DMPC) or dipalmitoylphosphatidylcholine (DPPC), cholesterol (CHOL) anddicetylphosphate (DCP) containing Amiodarone are prepared at pH 4.5using DMPC:CHOL:DCP (3:1:2 mol ratio) and are stable at this pH, and areless stable at the neutral pH of the heart. Because the stability of theliposome can be varied, and even triggered by external inputs, aspecific size of tissue may be treated locally with small molecules inthis fashion.

If the small molecule has a very short half-life, or antagonists havebeen delivered systematically to prevent the drug from having systemiceffects, such an approach will enable local delivery of small moleculesto regions of varying sizes within the myocardium. Alternatively, somesmall molecules may be delivered transiently only when needed, such asto terminate a cardiac arrhythmia, and so that systemic effects areminimized. Such systems could involve a permanently implantable infusionsystem for either continuous or transient local delivery as has beendescribed in the art.

Liposomal encapsulated agents delivered to the myocardium will alsoprovide advantages to other therapeutic agents. Liposomal encapsulationcan improve transfection of gene therapy preparations, and cytosolicdelivery of macromolecules. Liposomal delivery systems can be used toalter macromolecule and gene therapy pharmacokinetics and improve theirability to enter the cell cytosol. Delivery vehicles capable ofdelivering agents to the cell cytosol have been created in fusogenicliposomes, which enable them to cross the cell membrane in a lipophilicvesicle. Newer techniques for triggering the liposomes so that theircontents may be released within the cytosol have been developed, and abrief review of this work has appeared in the literature [OlegGerasimov, Yuanjin Rui, and David Thompson, “Triggered release fromliposomes mediated by physically and chemically induced phasetransitions”, in Vesicles, edited by Morton Rosoff, Marcel Dekker, Inc.,New York, 1996.] Because the liposome is not stable at thephysicochemical conditions within the body, it can be designed todegrade in a time period less than it takes to get to the cardiac lymphnode. Once the liposome is degraded, the body can address the liposomalcontents and break them up. Liposomes within the systemic circulationcan then be minimized, as will endocytosis of the macromolecules andgene therapy preparations outside the target region. No approach fordelivering such liposomal encapsulated agents to a depth within themyocardium has been described.

As described, the endocardial to epicardial, and apex to base lymphatictransport pathways can be used to deliver macromolecules and particulatedrug delivery systems to the targeted region in need of therapy. Theincreased risk of ischemia in the subendocardium implies that it is thetissue in need of therapeutic intervention. This has been hypothesisedas being due to the higher interstitial pressures during cardiacsystole, which may limit perfusion of this tissue region as opposed tosubepicardial tissue. In order to treat this region with therapeuticagents from a locally delivered depot site, delivery should be such thatendogenous transport pathways deliver agents to the target regions. Thiscan be accomplished by delivering agents on the endocardial side of theischemic zone, and towards the apex of the heart. Such an approach hasnot been previously described. The internal lymphatic system of theheart can also be used to control delivery of the therapeutic agentsthroughout the heart. For example, liposome encapsulated or micelleencapsulated amiodarone, or other anti-arrhythmic agents can be injectedinto the ventricle wall, (and the liposomes formulated for a half lifeof about five minutes to sixty minutes), whereupon the lymphatic systemwill transport the liposomes upward toward the atrium of the heart tothe vicinity of the cardiac lymph node. Lymphatic vessels flow adjacentto the atrium of the heart, such that agents delivered into theventricular wall will migrate to the atrium and the atrium wall. Thistransport happens within minutes, so that the release of the therapeuticmolecules will occur in the walls of the atrium. This has potential fortreating atrial arrhythmias. (Thus it can be appreciated that variationof the size of the encapsulated therapeutic agent can be employed inremarkable new therapies.)

The agents to be delivered may include small molecules, macromolecules,and gene therapy preparations. These will be briefly defined.

“Small molecules” may be any smaller therapeutic molecule, known orunknown. Examples of known small molecules relative to cardiac deliveryinclude the antiarrhythmic agents that affect cardiac excitation. Drugsthat predominantly affect slow pathway conduction include digitalis,calcium channel blockers, and beta-blockers. Drugs that predominantlyprolong refractoriness, or time before a heart cell can be activated,produce conduction block in either the fast pathway or in accessory AVconnections including the class IA antiarrhythmic agents (quinidine,procainimide, and disopyrimide) or class IC drugs (flecainide andpropefenone). The class III antiarrhythmic agents (sotolol oramiodorone) prolong refractoriness and delay or block conduction overfast or slow pathways as well as in accessory AV connections. Temporaryblockade of slow pathway conduction usually can be achieved byintravenous administration of adenosine or verapamil. [Scheinman,Melvin: Supraventricular Tachycardia: Drug Therapy Versus CatheterAblation, Clinical Cardiology Vol. 17, Supp. II-11-II-15 (1994).] Manyother small molecule agents are possible, such as poisonous or toxicagents designed to damage tissue that have substantial benefits whenused locally such as on a tumor. One example of such a small molecule totreat tumors is doxarubicin.

A “macromolecule” is any large molecule and includes proteins, nucleicacids, and carbohydrates. Examples of such macromolecules include thegrowth factors, Vascular Endothelial Growth Factor, basic FibroblasticGrowth Factor, and acidic Fibroblastic Growth Factor, although othersare possible. Examples of macromolecular agents of interest for localdelivery to tumors include angiostatin, endostatin, and otheranti-angiogenic agents.

A “gene therapy preparation” is broadly defined as including geneticmaterials, endogenous cells previously modified to express certainproteins, exogenous cells capable of expressing certain proteins, orexogenous cells encapsulated in a semi-permeable micro device. Thisterminology is stretched beyond its traditional usage to includeencapsulated cellular materials as many of the same issues ofinterstitial delivery of macrostructures apply.

The term “genetic material” generally refers to DNA which codes for aprotein, but also encompasses RNA when used with an RNA virus or othervector based upon RNA. Transformation is the process by which cells haveincorporated an exogenous gene by direct infection, transfection, orother means of uptake. The term “vector” is well understood and issynonymous with “cloning vehicle.” A vector is non-chromosomal doublestranded DNA comprising an intact replicon such that the vector isreplicated when placed within a unicellular organism, for example by aprocess of transformation. Viral vectors include retroviruses,adenoviruses, herpesvirus, papovirus, or otherwise modified naturallyoccurring viruses. Vector also means a formulation of DNA with achemical or substance which allows uptake by cells. In addition,materials could be delivered to inhibit the expression of a gene.Approaches include: antisense agents such as synthetic oligonucleotideswhich are complimentary to RNA or the use of plasmids expressing thereverse compliment of a gene, catalytic RNA's or ribozymes which canspecifically degrade RNA sequences, by preparing mutant transcriptslacking a domain for activation, or over express recombinant proteinswhich antagonize the expression or function of other activities.Advances in biochemistry and molecular biology in recent years have ledto the construction of recombinant vectors in which, for example,retroviruses and plasmids are made to contain exogenous RNA or DNArespectively. In particular instances the recombinant vector can includeheterologous RNA or DNA by which is meant RNA or DNA which codes for apolypeptide not produced by the organism susceptible to transformationby the recombinant vector. The production of recombinant RNA and DNAvectors is well understood and need not be described in detail.

Many delivery systems could be used to deliver these agents to a regionof the myocardial interstitium. During surgical procedures, a syringemay suffice, but it is more likely that a transvascular deliverycatheter such has been called out would be used to deliver theappropriate therapeutic agents to the appropriate sites. Essentially, asteerable catheter would be advanced to a location within the heartchamber and placed adjacent to the heart wall. The drug deliverycatheter would be advanced so that it penetrates the heart wall and thedesired volume of particulate delivery slurry or suspension (0.05 ml to2.0 ml) would be infused. The penetrating structure would be disengaged,and the drug delivery catheter would be pulled back a short distancewithin the delivery catheter. The steerable catheter would bereposition, and the process may be repeated a number of times if sodesired.

The benefits of the different controlled systems may also be combined.For example, to provide for local small molecule delivery that issustained over time, and does not require an indwelling drug deliverysystem in the heart chamber, the SUV liposomes containing the smallmolecules could be delivered within biodegradable microdrug deliverysystems such as larger more stable liposomes or other fully encapsulatedcontrolled release system, such as a biodegradable impermeable polymercoatings. The time course of release is governed then by the additivetime delay of the barriers that separate the therapeutic agent from thehost, as well as their combined transport pathways. Microsphere deliverysystems could also be used.

The ability to deposit therapeutic agents in to the myocardium foruptake into the cardiac lymphatic system, combined with the ability ofsome of the molecules discussed above to migrate from the lymphaticducts into parallel running arteries, permits introduction oftherapeutic agents for the coronary arteries to be introduced throughthis pathway. The result is a very low flow environment for theintroduction of anti-stenotic compounds and other arterial therapeuticagents, as compared to the infusion of therapeutic agents into the highflow environment of the coronary arteries themselves. The methodillustrated in FIG. 5 is useful to deliver therapeutic agents to thecoronary arteries, such as the left coronary artery and its branches,including the left anterior descending coronary artery, and the rightcoronary artery and its branches. As illustrated in FIG. 5, cathetersystem 9 with centrally located drug delivery catheter 20 implanted at adepth within the left ventricular apex 15 of the heart 10. Hollowpenetrating structure 30 has penetrated the heart muscle from theendocardial side. The artery to be treated, in this case the circumflexbranch of the left coronary artery 500, courses over the surface of theheart (chosen for illustration purposes only). A correspondingepicardial lymphatic vessel 501 runs nearby, and many sub-epicardiallymphatic vessel such as vessel 502 drain into the epicardial lymphaticvessel. (It should be noted that the cardiac lymphatic vessels are bothnumerous and largely uncharted, and may be highly variable from personto person). The artery is occluded by an arterial plaque, cholesterol orstenotic mass 505 which is amendable to treatment with drug therapies.The artery may have been previously treated with angioplasty, or a stentmay have been placed For example, balloon angioplasty is illustrated inFIG. 6, which shows an angioplasty catheter 520 with a balloon 521mounted its distal tip, placed within the artery 500 in the area of alesion (mass 505, for example). Expansion the lesion with theangioplasty balloon may precede treatment with catheter 510. Likewise,as illustrated in FIG. 7, a stent 530 may be placed within the region ofthe blood vessel occluded by a lesion (mass 505, for example). Bothmethods of treatment are often accompanied by injury to the surroundingblood vessel and restenosis. the occlusion. In any case, several drugsare available to either ameliorate the blockage or prevent restenosis orre-occlusion after balloon angioplasty and/or stent placement. Thedelivery catheter is navigated into the endocardial space of the leftventricle 510, and secured in place with penetrating structure 30. Asmall dose of therapeutic agent, indicated by the molecules 35, isinjected into the myocardium, and the penetrating structure iswithdrawn. (Withdrawal of the penetrating structure may be delayed asnecessary to prevent the therapeutic agent from draining back into theventricular space.) The molecules of the therapeutic agent are taken upby the lymphatic system, entering into vessels 501 and 502, andtransported upwardly. The molecules also migrate out of the lymphaticsystem and then migrate into the nearby coronary artery, followingmultiple paths indicated by the arrows in FIG. 5. The moleculespenetrate the adventicia, or outer layer, of the coronary artery, andthus enter the coronary artery. Molecules enter the coronary arteryalong the entire length that runs near the lymphatic vessels whichinitially take up the molecules. Thus, therapeutic agent enters thecoronary blood vessel at the site of occlusion and proximally to theocclusion, after having been injected into a more distal location(relative to the coronary artery). The term entering the artery mayinclude entering the arterial wall without entering the lumen of theartery, or passing through the arterial wall into the lumen of theartery. While the method is illustrated in relation to the leftcircumflex coronary artery, it may be used with all the coronaryarteries. Also, while endocardial access is preferred for the method asapplied to the coronary arteries located on the anterior surface of theheart (left and right coronary arteries). Therapeutic agents may bedeposited into the myocardium through catheters delivered into thecoronary sinus, the coronary veins, and even the coronary arteries,including the coronary artery subject to treatment by angioplasty orstent placement. Additionally, while it is preferable to accomplish thetherapy percutaneously, the method may be accomplished by injection intothe heart, epicardially, during open surgery, or during endoscopic orkey-hole surgery through the chest.

Various therapeutic agents can be delivered to the coronary arteriesusing this approach. Anti-restenosis agents may include agents whichinhibit smooth muscle proliferation, endothelial cell proliferation, andgrowth of other components of arterial plaque and stenosis, antioxidantdrugs, anti-inflammatory drugs, platelet derived growth factorantagonists, and numerous other proposed compounds. Anti-restenosisagents also include anti-neoplastic agents such as taxol, statins (suchas Lovastatin and Provastatin), Pemirolast, Tranilast, Cilostrazol,INOS, ENOS, EC-NOS, and gene therapy formulations. All of these agentsmay be formulated as time-release or controlled release formulations fordelivering these molecules by deposition in the myocardium in positionfor uptake and eventual migration into a target site in the coronaryarteries. The therapeutic agents may be incorporated into biodegradablemicrospheres with a diameter larger than 15 um (and preferably greaterthat 50 um) in diameter so that a depot can be placed distal to theregion of the vessel where treatment is desired for sustained deliveryto the target vessel for extended periods, such as several hours orseveral of weeks. The microspheres would elute agents into themyocardium slowly over a period of time in order to enable the sustaineddelivery through the lymphatics of the heart. In many cases themolecules may be linked to other molecules such as carbohydrates toprevent their intravasation and convective losses to the blood. Themicrospheres, which are sized to restrict their migration, degradewithin the myocardium near the deposition site and release agents whichthen migrate through the lymphatics and migrate from the lymphatics tothe adventicia and cells within the vascular wall within the targetregion of the coronary vessel. For other therapies, gene therapypreparations are delivered to infect the cardiac myocytes in order totransfect the RNA for production of the therapeutic proteins locallywhich will then migrate through the lymphatic walls to treat the targetvessel peri-adventicially.

The microspheres used in this method are preferably sized to inhibitmigration and immediate uptake by the lymphatic vessels, and arepreferably 50 um in diameter and greater, but perhaps as small as 30 um.Agents could be encapsulated in liposomal structures with diametersranging from 50 to 600 nm which are transported by the lymphatics anddesigned to break up at physiological pH such that agents are releasedwhich are able to diffuse through the lymphatic and arterial walls.

Anti-angiogenic agents could also be used to limit the angiogenicresponse which has been recently associated in the literature withatherosclerotic plaques. The hypothesis that anti-angiogenic agents maylimit restenosis could be used during a revascularization procedure inwhich angiogenic agents are delivered along with anti-angiogenic agentsat the time of stent placement. By having the anti-angiogenic agents bethe first delivered they would transport through the lymphatics and tothe region of injury caused by balloon angioplasty or stent placementand minimize the restenosis. Although the reservoir of microspherescontaining angiogenic agents may be delivered at the samecatheterization procedure used to accomplish angioplasty to stentplacement, and potentially at the same location, they would be releasedafter the anti-angiogenic and anti-neoplastic agents have had theireffect for limiting restenosis. Thus dosage forms for anti-angiogenicagents and angiogenic agents could be placed in the heartsimultaneously. One way of doing this would be to have a microsphere inwhich the core contains angiogenic agents and the outer shell containsanti-angiogenic agents. Another method of doing this is to supplyanti-angiogenic agents in solution or in small microspheres which areimmediately taken up in the lymphatic vessels, while supplying theangiogenic agents in larger microspheres which will not be taken up. Themethod thus comprises treating a coronary blood vessel with stentplacement, balloon angioplasty, or both, and delivering a dose oftherapeutic agent to the site of treatment, where the therapeutic agentis delivered to the myocardium at a location distal to the site oftreatment, and the therapeutic agent includes anti-angiogenic agent tobe released in a time frame shortly after treatment and angiogenic agentto be released in a time frame after release of the anti-angiogenicagent. Alternately, the anti-angiogenic agent can be delivered to thetarget site with the angioplasty balloon or stent, by coating theballoon or stent with the anti-angiogenic agent, while the angiogenicagent is deposited in the myocardium for delayed transport to the targetsite.

Thus, the method allows the use of the lymphatic vessels and endogenouslymphatic transport to carry agents from the myocardially located depotof therapeutic agents to the target coronary arteries such that agentsare delivered through the target vessel walls peri-adventicially. Thisprovides a means of delivering therapeutic agents peri-adventitially tothe vessels of the heart that is far superior to surgical placement of aperi-adventitial controlled release devices, and delivery of agents tothe space between the pericardial space between the parietal andvisceral pericardium.

While the inventions have been described in relation to the treatment ofcardiac tissue, it should be appreciated that the compounds and methodsof treatment may be applied to various body tissues. Thus, while thepreferred embodiments of the devices and methods have been described inreference to the environment in which they were developed, they aremerely illustrative of the principles of the inventions. Otherembodiments and configurations may be devised without departing from thespirit of the inventions and the scope of the appended claims.

1. A method of preventing restenosis in a artery by delivering atherapeutic amount of antirestenotic agents selected from the set ofantiproliferative agents which inhibit smooth muscle proliferation,endothelial proliferation, endothelial cell proliferation, and growth ofother components of arterial plaque and stenosis locally to the coronaryarteries via controlled release biodegradable polymers.
 2. The method ofclaim 1 in which said polymers are implanted periadventicially proximatethe artery.
 3. The method of claim 1 in which the vessel is a coronaryartery.
 4. The method of claim 3 in which the agents are deliveredintramyocardially and migrate to a periadventicial location.
 5. A methodof preventing restenosis in a artery by delivering a therapeutic amountof agent selected from the set of statin agents, anti-inflammatoryagents, antioxidant agents, Pemirolast, Tranilast, cilostrazol, INOS,ENOS, and ECNOS, locally to the coronary arteries via controlled releasebiodegradable polymers.
 6. The method of claim 5 in which said polymersare implanted periadventicially proximate the artery.
 7. The method ofclaim 5 in which the vessel is a coronary artery.
 8. The method of claim7 in which the agents are delivered intramyocardially and migrate to aperiadventicial location.